ASCO The selective estrogen-receptor modulator (SERM) toremifene(Drug information on toremifene) (Acapodene), used to treat advanced breast cancer, halved the risk of prostate cancer at 1 year in men with high-grade prostatic intraepithelial neoplasia (PIN), a randomized, double-blind, placebo-controlled multicenter study has found. Toremifene also was safe and well tolerated, investigators reported. The findings are significant in that 30% to 40% of men with PIN are diagnosed with prostate cancer within 1 year, but treatment for PIN is not available; it is simply monitored until it progresses to cancer, said lead investigator David Price, MD. "This is the first time a drug has shown promise for lowering the incidence of prostate cancer in men with PIN," he said.
Dr. Price, director of urologic oncology and clinical research, Regional Urology LLC, Shreveport, Louisiana, reported the findings at the 41st Annual Meeting of the American Society of Clinical Oncology (abstract 1003).
"For the last 100 years," he said, "our treatments for prostate cancer have primarily been directed toward testosterone . . . but it has become increasingly evident that estrogens(Drug information on estrogens) also play a role in the initiation of prostate cancer," because as prostate cancer incidence increases with age, so does men’s ratio of estrogen to testosterone. "In this study," he noted, "we targeted estrogens, to see whether inhibition of estrogen receptors in the prostate could prevent or delay the onset of prostate cancer."
The trial represents the largest prospective study of the natural history of PIN, he added, noting that men with PIN are at much greater risk for prostate cancer than those with elevated PSA (prostate-specific antigen).
A total of 514 patients with biopsy-diagnosed high-grade PIN and no evidence of prostate cancer were randomized at 64 sites to oral toremifene at 20, 40, or 60 mg or placebo once daily, for 12 months. The four study groups were similar in patient age (average, about 65 years), height and weight, race distribution (black vs white patients), total and free PSA levels, prostate volume, testosterone and estradiol(Drug information on estradiol) levels, and number of cores taken on prestudy biopsies.
Men were rebiopsied at 6 and 12 months (with at least eight cores taken per biopsy). Initial and subsequent biopsies were evaluated by a central pathologist for diagnosis of high-grade PIN and prostate cancer. Investigators compared cumulative risk reduction (using Mantel-Cox analysis) and 12-month-point estimated risk reduction (by Cochran-Mantel-Haenszel analysis) between groups at each toremifene dose and placebo, stratified by study center.
A total of 447 patients were evaluable (ie, had at least one on-study biopsy and were compliant with the protocol). At the 6-month point, the cumulative incidence of prostate cancer at the 20-mg toremifene dose was not significantly different from the placebo group (15.9% vs 15.7%, respectively); this was not unexpected and was most likely accounted for by initially missed cancer, Dr. Price explained. Men diagnosed with prostate cancer at 6 months were removed from study, for a total of 342 patients evaluable at 12 months.
Among patients treated for 6 months, the cumulative incidence of prostate cancer at 1 year was 24.4% in patients randomized to toremifene at 20 mg vs 31.2% in the placebo group (P < .05). This 22% decrease in incidence seen with 20 mg toremifene translated into approximately 6.8 cancers prevented per 100 persons treated per year, the investigators reported. The cumulative incidence of prostate cancer with the 40 mg and 60 mg doses also was lower, compared with placebo, but it was not significantly different (28.2% and 28.1%, respectively).
Among patients who completed an entire year of treatment (those with no evidence of prostate cancer at baseline and at 6-month biopsies), the incidence of prostate cancer was reduced by 48% with toremifene 20 mg vs placebo on 12-month biopsy (9.1% vs 17.4% incidence, P = .045). For the 40-mg and 60-mg doses, cancer incidence at 1 year was 14.3% and 13.0%, respectively, a nonsignificant difference vs placebo.
"In this study, the initiating dose of toremifene was 60 mg, because that is the FDA-approved dose in breast cancer," Dr. Price said. "Normally, you would escalate the dose, but in our study the dose was de-escalated, based on animal data suggesting lower doses of toremifene may, in fact, be better." A possible reason the lower toremifene dose is superior to higher doses, he explained, is that at lower doses (eg, at concentrations around 0.1 µM), toremifene has been found to have an antagonistic effect primarily on ER subtype alpha rather than the ER beta subtype, "and it’s becoming increasingly evident that the ER alpha receptor subtype may play a more important role in prostate carcinogenesis."
The incidence of serious adverse events in the three toremifene groups was "roughly equivalent to that seen with placebo, as were drug-related side effects," although fatigue was reported in 5% of patients randomized to toremifene vs 3% of men in the placebo group, he said. Toremifene did not appear to stimulate progression of cancer. No differences were seen in Gleason scores with placebo vs toremifene; in fact, there was a trend toward a lower percentage of Gleason scores of 7 or more with toremifene.
A confirmatory, multicenter, placebo-controlled phase III study is ongoing, and results are expected in the first quarter of 2006, Dr. Price said.